ABSTRACT Skin cancer is the most common cancer in the US and worldwide with a continually increasing incidence 22,23. Exposure to ultraviolet B radiation (UVB) from the sun is the major environmental risk factor causing skin cancer. In addition to causing DNA damage and increased mutation burden, UVB also causes the inflammatory damage response, which can also contribute to tumorigenesis. In the past decades, tremendous progress has been made in elucidating the mechanism of skin cancer development, including the role of inflammation. However, our understanding of the molecular mechanism regulating UVB damage response and skin cancer is still limited. Recently, we have discovered a novel role of YTHDF2, an N6-methyladenosine (m6A) RNA methylation reader, as an autophagy target, in suppressing UVB-induced inflammation and tumor growth. m6A RNA methylation is the most abundant internal chemical modification in eukaryotic messenger RNA (mRNA) as well as non-coding RNA (ncRNA). m6A modification regulates the fate of RNA and its functions, such as RNA stability, translation, nuclear processing, and RNA-protein interactions. Guided by our preliminary data and published work, we hypothesize that YTHDF2, as an m6A reader, suppresses UVB-induced damage response and skin tumorigenesis through post-transcriptionally regulating RNA stability. To test this hypothesis, we will employ several new methods including transcriptome-wide m6A mapping, eCLIP-seq, and RIP-seq, as well as a new mouse model with skin-specific YTHDF2 deletion. Our hypothesis will be tested in three Specific Aims. Aim 1 will determine the mechanism by which YTHDF2 regulates UVB damage response and tumorigenicity. Aim 2 will determine the mechanism by which UVB down-regulates YTHDF2 through autophagy. Aim 3 will determine the consequences of YTHDF2 inhibition in UVB damage response and skin tumorigenesis using mice with keratinocyte-specific deletion of YTHDF2. Successful completion of our proposed work will vastly expand our knowledge on the regulation of UVB damage response and tumorigenesis by YTHDF2 and RNA metabolism, and may provide new opportunities for developing better strategies to prevent and treat skin cancer by targeting the YTHDF2 pathway. Given the emerging critical role of inflammation in multiple cancers, our work here in inflammation and YTHDF2 is not only significant for skin cancer, but may also be applicable to other epithelial tumor types as well.